Industrial exposure to cadmium and lead is a widespread and serious occupational problem. This proposal is directed toward evaluating the effects of these two metals in single and combined exposure, on several levels: 1) in the human subject, 2) in experimental animals and 3) in in vitro test systems. It is proposed that those workers at risk because of occupational contact with these two heavy metals be examined to determine if there are abnormalities of renal function and of skeletal function that will serve as hallmarks of early toxic efects, prior to the development of established (and potentially irreversible) disease. Furthermore, utilizing the clearance and micropuncture techniques as well as quantitative histomorphometry in the experimental animal, both the acute and chronic effects of lead and cadmium on the kidney and bone can be evaluated. The causes and mechanisms of the toxic effects of these substances will be studied at the cellular level with the in vitro techniques of isolated tubular perfusion and brush border vesicle studies. If successful, these experiments should provide better early warning detection systems for toxic effects of lead and cadmium and should add to our basic knowledge as to how their toxic effects are mediated. An understanding of the pathogenetic sequence should not only aid in the prevention of disease by exposure avoidance, but may allow us to manipulate the intenal as well as external environment so that these substances may be rendered less harmful if inhaled or ingested. Furthermore, better treatment modalities for subjects intoxicated with lead or cadmium should result from the prosecution of the studies outlined in this proposal.